rs76304838

Variant names:

• chr2-227261062-T-C
• rs76304838
• NM_000091.5:c.1115-20T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000091.5(COL4A3):​c.1115-20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00638 in 1,603,440 control chromosomes in the GnomAD database, including 559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (286 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (273 hom.)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.111
• Publications: 2 publications found

Genes affected

COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jun 2010]

MFF-DT (HGNC:41067): (MFF divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 2-227261062-T-C is Benign according to our data. Variant chr2-227261062-T-C is described in ClinVar as Benign. ClinVar VariationId is 254975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000091.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	NM_000091.5	MANE Select	c.1115-20T>C		intron	N/A	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.1487-1779A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.1115-20T>C		intron	N/A	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.1487-1779A>G		intron	N/A
	COL4A3	ENST00000871618.1		c.1115-20T>C		intron	N/A	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.0342 AC: 5208 AN: 152210 Hom.: 285 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.00865 AC: 2155 AN: 249242 AF XY: 0.00646

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.00516

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000522

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00345 AC: 5007 AN: 1451112 Hom.: 273 Cov.: 28 AF XY: 0.00298 AC XY: 2153 AN XY: 722760

African (AFR) AF: 0.123 AC: 4054 AN: 33082

American (AMR) AF: 0.00590 AC: 264 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.000174 AC: 15 AN: 85998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00539 AC: 31 AN: 5748

European-Non Finnish (NFE) AF: 0.000199 AC: 219 AN: 1102452

Other (OTH) AF: 0.00698 AC: 419 AN: 60028

GnomAD4 genome AF: 0.0343 AC: 5219 AN: 152328 Hom.: 286 Cov.: 33 AF XY: 0.0329 AC XY: 2450 AN XY: 74494

African (AFR) AF: 0.119 AC: 4965 AN: 41558

American (AMR) AF: 0.0114 AC: 175 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68034

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0149 Hom.: 28

Bravo AF: 0.0383

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.8
DANN	Benign	0.90
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs76304838;

hg19: chr2-228125778;